Lecture 4: Alcohol+ Protein Metabolism Flashcards
(58 cards)
1
Q
Case study: Pesticide Poisoning. Guy has continued exposure to aromatic weak acids (e.g. DNC).
Symptoms = Low body temp, no subcutaneous fat. Explain symptoms.
A
- aromatic weak acids readily penetrate the mitochondrial membrane & act as uncoupling agents
- collapses p.m.f and uncontrolled metabolism occurs
- large amount of metabolic fuel (fatty acids) + O2 used
- less ATP, more heat = high body temp = sweating to cool down
2
Q
Ketogenic a/a
A
Lysine, Leucime
3
Q
Both glucogenic and ketogenic
A
Tyrosine, Threonine, Phenylalanine
4
Q
Which a/a do pregnant women and children need more of? (Conditionally essential)
A
Arginine, thyrosine, cysteine
5
Q
Where do carbon atoms for non-essential a/a come from?
A
- intermediates of glycolysis (C3)
- PPP (C4&C5)
- Krebs Cycle (C4&C5)
6
Q
Why is removal of nitrogen from a/a important?
A
To allow carbon skeleton of a/a to be metabolised
7
Q
How is NH3 toxic (Hyperammonaemia) and state symptoms.
A
- associated with blurred vision, tremors, coma, death
- Disrupts energy supply to brain
- affects pH and interferes with neurotransmitter release n synthesis
8
Q
Which aminotransferase enzyme is routinely measured to test for liver damage?
A
- ALT (Arginine Aminotransferase)
- AST (Aspartate Aminotransferase)
9
Q
What is the difference between homocysteine and homocystine
A
- Homocystine is two homocysteine molecules joint by a disulphide bond.
- Homocystine is the oxidised form of homocysteine
10
Q
What is the mode of inheritance of homocystinuria?
A
Autosomal recessive
11
Q
How would PKU disrupt blood brain barrier?
A
- Phenylalanine is a large neutral amino acid (LNAA) and competes for transport across the blood brain barrier via LNAAT.
- Excess phenylalanine saturate this transporter
- Inhibiting protein/neurotransmitter synthesis = brain development affected.
12
Q
Briefly explain how the metabolism of alcohol can cause damage to the liver.
A
- Intermediate metabolite, acetaldehyde is a toxic metabolite.
- Increased acetyl coA, more fat synthesized, converted to triacylglycerol. Decreased NAD/NADH ratio. No oxidation of FA.
- Less lipoproteins formed. Unable to transport fat out of liver. Results in ‘fatty’ liver.
13
Q
Desc. the metabolism of alcohol
A
Ethanol —> Acetaldehyde —> Acetate
[alcohol dehydrogenase] [aldehyde dehydrogenase]
- Acetate –> acetyl CoA (enter TCA or FA synthesis)
14
Q
What is the recommended limit of alcohol for both men and women in a week? What is the kinetics displayed by alcohol removal?
A
- 14 units spread over 3 days in a week
- Exhibits zero-order kinetics (eliminated in linear fashion) = undergo constant removal regardless of plasma conc.
15
Q
Which compound formed in alcohol metabolism is toxic and what keeps its effects to a minimum?
A
- Acetaldehyde
- Aldehyde dehydrogenase has a very low Km
16
Q
How does alcohol damage affect liver?
[3 disease]
A
- Fatty liver
- Alcoholic hepatitis
- Alcoholic cirrhosis (damage)
17
Q
What is the response to chronic alcohol consumption?
A
- Decrease NAD+ –> lactate X converted to pyruvate –> lactate ⬆️ –> lactic acidosis + kidney ability to excrete uric acid ⬇️–> monosodium urate crystals form –> phagocytes remove, die –> release lysosomal enzyme –> cell lysis & inflammation –> gout
- Decrease NAD+ –> X glycerol metabolism –> ⬇️gluconeogenesis –> hypoglycaemia
- Increased acetyl~CoA –> ⬆️FA + ketone bodies + TAG –> lower lipoprotein synthesis –> fatty liver
18
Q
Explain the mechanism of action of Disulfiram
A
- Inhibit aldehyde dehydrogenase –> acetaldehyde accumulate –> ‘hangover’
- Used with other methods to stop drinking
19
Q
What diseases are oxidative stress linked to?
A
- Cardiovascular disease
- Alzheimer’s disease
- Rheumatoid arthritis
- Multiple sclerosis
- Cancer
- COPD
20
Q
What are free radicals?
A
An atom/molecule that has unpaired electrons and is very reactive
21
Q
What are RNS and give some examples
A
- Superoxide react w NO to form peroxynitrite
- Not a free radical –> powerful oxidant
22
Q
What are ROS and give some examples
A
- Superoxide and Hydroxyl radical
- H2O2 X a radical but react with Fe2+ to produce radicals
23
Q
How does ROS affect DNA?
A
- Reacts with base: lead to mispairing –> mutation
- Reacts w sugar: Strand break/mutation
- Mutation can lead to cancer
24
Q
How does ROS cause damage to proteins?
A
- Reacts w proteins –> disulphide bond form –> fragment/ change in protein structure –> loss of function/change of func –> protein degradation
- Lead to misfolding/crosslinking –> Heinz bodies in RBC
25
What is the function of disulphide bonds?
- Important role in folding and stability of proteins
| - Formed between thiol groups of cysteine
26
How does ROS damage lipids? x2
- Lipid peroxidation (atherosclerosis)
- ROS react w polyunsaturated FA --> lipid radical/ lipid peroxyl radical (after O2) --> chain reaction, react with more FA by extracting H atom --> Lipid bilayer integrity fails
27
What are some sources of biological oxidants?
Endo:
- ETC
- Peroxidases
- NADPH oxidases
- NO oxidases
Exo:
- Radiation
- Drugs (Primaquine, anti-malarial)
- Pollutants
- Toxins (Paraquat, herbicide)
28
How is the ETC a source of ROS?
- Occasionally electrons escape ETC --> react w O2 --> superoxide
29
What is a respiratory burst?
- Rapid production of superoxide and H2O2 by phagocytes to kill bacteria
- Neutrophils and monocytes
30
What is chronic granulomatous disease?
- Genetic defect in NADPH oxidase complex --> ⬆️risk to bacterial infections
- Pneumonia, Impetigo (skin infection), cellulitis (infection in deeper layer of skin)
31
What are some cellular defences against ROS and RNS?
- Superoxide dismutase (SOD):
i) Converts superoxide to H2O2 and O2
- Catalase:
i) Converts H2O2 to H2O & O2
II) Declining levels associated w grey hair
- Glutathione:
i) Thiol group of Cys- donates e- to ROS
ii) Reacts with another GSH to form disulphide
[catalysed by glutathione peroxidase]
*requires selenium
iii) GSH reduced back by glutathione reductase --> transfer e- to NADPH
32
What vitamins are cellular defences and how?
- Vit E: Prevent peroxidation --> reduce free radical by donating H atom in nonezymatic reaction
- Vit C: Regenerate reduced form of Vit E
BONUS: Carotenoids, Uric acid, Melatonin
33
What are Heinz bodies?
- Hb in RBC form disulphide bonds --> aggregates
- Increased mechanical stress when squeezing through capillaries
- Sign of G6PDH deficiency
- Removed by spleen
34
How does paracetamol cause damage? How is overdose treated?
- High levels --> NAPQI ⬆️--> Lipid peroxidation, damage to proteins + DNA
- Acetylcysteine replenish glutathione levels
35
Why is creatinine measured?
- Breakdown product of creatine/creatine.P
- Produced at a constant rate, proportional to muscle mass
- Indicator of renal function: raised plasma level + low urine level = damage to nephrons
Bonus: Plot graph of 24hr urine creatinine muscle mass X muscle mass
36
Describe the different types of nitrogen balance
1. N equilibrium: Intake = Loss
[Normal state, No change in body protein]
2.Positive N balance: Intake > Loss
[Growth/Pregnancy/Recovering from malnutrition, ⬆️in total body protein]
3. Negative N balance: Intake < Loss
[Never normal/Trauma/Infection/Malnutrition, ⬇️body protein]
37
Name glucogenic, ketogenic and both a.a & desc. their function
- Glucogenic: Alanine
(a. a can be used to make glucose)
- Ketogenic: Lysine, Leucine
(a. a can be used to make ketone bodies, acetyl CoA)
- Both: Tyrosine
38
When does mobilisation of protein reserves occur? What inhibits/stimulates it?
- Occurs in liver
- Extreme stress (starvation)
- Inhibit: Insulin + GH, Stimulate: Cortisol (glucocorticoid)
39
What are the conditionally essential a.a?
- Children and pregnant women
| - ACT = Arginine, Cysteine, Tyrosine
40
Where does the carbon atoms for a.a synthesis come from?
- TCA cycle
- PPP
- Glycolysis
41
Where does the amino group for the synthesis of a.a come from?
- Transamination from other a.a
| - Ammonia
42
What is tyrosine, cysteine and tryptophan used to synthesise?
- Tyrosine: T3,T4 & melanin
- Cysteine: Glutathione
- Tryptophan: Melanin
43
Why is removal of nitrogen from a.a essential? Which pathways facilitate the removal?
- Allow carbon skeleton of a.a --> oxidative metabolism
- Nitrogen --> urea
- Pathways: Transamination & Deamination
44
What is transamination? What enzyme catalyses the reaction, what is their mode of action?
- Transfer amine group from one a.a to another
- Aminotransferase enzyme use α-ketoglutarate --> trf to glutamate
- Require coenzyme pyridoxal phosphate (Vit B6)
45
What are some key aminotransferase enzymes? What do they test for?
- Alanine (ALT), Aspartate (AST)
- Liver function test
- High in conditions: Viral hepatitis, toxic injury, autoimmune liver disease
46
What is deamination? Where does it occur? Give some examples of enzymes that can perform deamination.
- Changes amino group --> ammonia (very toxic) --> urea
- Done in liver and kidney
- Keto acids --> metabolism
- Enzymes: Glutamate dehydrogenase, glutaminase
47
Features of urea
- High N content
| - Inert, water sol, excreted in urea, osmotic role
48
Where does the urea cycle occur? What regulates it?
- Occur in liver & 5 enzymes
| - High protein diet activate enzyme, Low represses it
49
What are some consequences and causes of defects in the urea cycle?
- Autosomal recessive genetic disorders deficiency in one of enzymes
- Leads to: hyperammonaemia, accumulation of urea cycle intermediates
50
What are some symptoms of defects in urea cycle and its treatment?
- Symptoms: Vomiting, Lethargy, Mental retardation, Seizures, Coma
- Low protein diet, replace a.a with keto acids
N.B Severe case = die, Mild = symptoms show late
51
Why is ammonia toxic?
- Readily diffusible, toxic to brain
- Affects pH (alkaline)
- Interfere w TCA cycle/ protein synthesis
52
What are mechanisms used to transport a.a?
1. Glutamine
- A.a + glutamate --> glutamine
- Transported in blood, cleaved by glutaminase (form glutamate & a.a --> urine)
2. Alanine
- Amine group transfered to glutamate (transamination) --> T. to pyruvate forms alanine
- Alanine (blood) --> liver convert back to pyruvate --> amino group (urea) + pyruvate (TCA)
53
How are defects in a.a metabolism detected and treated? What are some examples?
- Rare
- Heel prick test
- Phenylketonuria (PKU),
- Homocystinuria
- Treatment: X a.a in diet, modify diet at early age (effect less)
54
What is phenylketonuria (PKU)? Treatment?
- Deficiency in phenylalanine hydroxylase
- Accumulation of phenylalanine in tissue --> phenylketones in urine
- T: Low PhA diet enriched w tyrosine, avoid artificial sweeteners + high protein foods (milk, meat, eggs)
55
What are the affected pathways in PKU and what are its symptoms?
- X phenylalanine hydroxylase --> PhA X converted to tyrosine --> X T3,T4, melanin synthesis
- S: microcephaly (small head), hypopigmentation, intellectual disability, delayed development
**CAN BE AVOIDED W EARLY INTERVENTION
56
What is homocystinuria? Treatment?
- Problem breaking down methionine --> ⬆️homocystine
- Autosomal recessive
- Defect in cystathionine β-synthase
- T: low methionine diet, avoid high protein foods, X nuts, cysteine/vit B6 supplement
57
Effect of homocystinuria?
- Accumulation of homocysteine due to cystathionine β-synthase deficiency (require vit B6 co-factor)
- Elevated H.C --> cardiovascular disease
58
How does protein turnover occur?
1. Free amino acids from proteolysis of muscle proteins and digestion (also used for synthesis of muscle proteins)
2. Free a.a go to the liver --> amino group removed form urea --> urine
3. Free a.a --> carbon skeleton used (glucogenic + ketogenic) --> energy
